Approaching a Cure for AIDS Jeffrey Laurence, M.D. Senior Scientific Consultant for Programs, amfAR Professor of Medicine, Weill Cornell Medical College www.amfar.org www.amfar.org Defining an AIDS Cure Definition: “Treat a disease such that the patient no longer needs to continue treatment, as opposed to suppression or management of the disease as is presently required in diabetes, rheumatoid arthritis, and HIV.” * Specific: Functional vs. sterilizing cures *Fauci A. XVIIth International AIDS Conference, www.amfar.org Mexico City, Aug 3-8, 2008, Abst WESS0101 1 We want to cure HIV. “Viruses can’t be cured.” “Viruses can’t be cured…so far” •In 2009, NIAID spent $41million on HIV cure research, 3% of budget •(~$600million spent on vaccine research) •amfAR filling the gaping hole www.amfar.org A Cure for AIDS •AS Fauci: “We need a cure for AIDS.”* •ART is a life-long commitment •Current ART, and likely every newly developed antiretroviral drug, will have long-term, potentially life-limiting, adverse effects •2.7 million people were newly HIV infected in 2007, with ART reaching only 30% of those who needed it •It is unlikely that we can treat our way out of this pandemic: For every person started on ART, 2-3 are newly infected *Fauci A. XVIIth International AIDS Conference, www.amfar.org Mexico City, Aug 3-8, 2008, Abst WESS0101 2 “The U.S. spends about $20 billion every year on AIDS (both for programs in the U.S. and globally). The money is keeping millions of people alive around the world and preventing millions of infections. But a cure is needed, and it is unacceptable that something less than 0.5% (less than about $100 million) of U.S. spending on AIDS is funding AIDS cure research.” -The AIDS Policy Project, 2010 www.amfar.org www.amfar.org 3 Low-level Persistent Viremia in Patients on Suppressive ART Plasma HIV-1 RNA (copies/ml) RNA HIV-1 Plasma Palmer S, et al. Proc Natl Acad Sci USA 2008;105:3879-3884 www.amfar.org FOUR APPROACHES TO A CURE FOR AIDS 1.Change a person’s immune system Alter a person’s immune system so that cells normally vulnerable to HIV infection are rendered invulnerable. The major focus for such research is the HIV co-receptor CCR5, and there are two approaches: a stem cell transplant with a CCR5-/- donor (the “Berlin patient”), and gene therapy to render a person’s own stem cells CCR5-/-. 2.Identify and activate HIV reservoirs Induce active HIV replication in long-lived, latently-infected HIV cells so that they can be detected and killed 3.Selectively kill latently-infected HIV reservoirs 4.Treatment intensification Some studies suggest that very low levels of HIV replication (<1 copy/ml plasma) persist despite HAART, in peripheral blood and/or tissue reservoirs (such as the gut and CNS). This may contribute to maintenance of a latent state of infection, and be amenable to addition of new anti-HIV drugs. www.amfar.org 4 Chemokine Receptors and HIV-1 Cell Tropism Hoffman TL, Doms RW. Mol Membrane Biol 1999;16:57-65 www.amfar.org Homozygous ∆32 Deletion in 2nd extracellular loop of CCR5 in humans leads to HIV-1 resistance Liu R, et al. Cell 1996; 86:367-377 www.amfar.org 5 “A Doctor, a Mutation, and a Potential Cure for AIDS” Schoofs M. Wall Street Journal, November 7, 2008, p. A13 “The case was presented to scientists earlier this year at the Conference on Retroviruses and Opportunistic Infections. In September, the nonprofit American Foundation for AIDS Research, amFAR, convened a small scientific meeting on the case. … The scientists agreed that the patient is ‘functionally cured.’” www.amfar.org www.amfar.org 6 ●Chemotherapy: fludarabine (30mg/m2) araC (2g/m2) amsacrine (topoisomerase II inhibitor, 100mg/m2) cyclophosphamide (60mg/kg) ●Anti-thymocyte globulin (20mg/kg) ●Total Body Irradiation (2-4 Gy) ●GVHD prophylaxis: cyclosporine A, mycophenolate mofetil FLAMSAHAART continued: CONDITIONING efavirenz, REGIMEN FTC, tenofovir www.amfar.org www.amfar.org 7 Treatment of HIV-1 by allogeneic CCR5∆32/∆32 SCT Hutter G, et al. CROI 2008, Abst 719 www.amfar.org www.amfar.org 8 Treatment of HIV-1 by allogeneic CCR5∆32/∆32 SCT Hutter G, et al. CROI 2008, Abst 719 www.amfar.org www.amfar.org 9 ELISPOTs for interferon-γ (per 100,000 PBMCs) day -20 day +152 HIV 30 0 CMV 100 100 www.amfar.org www.amfar.org 10 “AIDS Patient is Reported Cured in Berlin with a Rare Treatment” McNeil DG Jr. New York Times, November 14, 2008, p. A12 “’It’s very nice, and it’s not even surprising,’ said Dr. Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases. ‘But it’s just off the table of practicality.’ [Yet] Doctors say the case gives hope for therapies that artificially induce the Delta32 mutation.” www.amfar.org Frequency of the CCR5-delta 32 Allele in Defined ETHNIC GROUP ALLELE FREQUENCY (%)* SwedishPopulations* 13.7 Russian 13.6 Australian 11.8 British 11.7 Spanish 9.8 French 8.9 Italian 5.5 Greek 4.4 Middle Eastern 0.0 Pueblo/Cheyenne Indian 0.0 Korean/Chinese 0.0 African/African-American 0.0 Oceanic 0.0 *Am J Hum Genet 62:1507, 1998 www.amfar.org 11 www.amfar.org Investigators Sponsors Vector Transduced Genes Encode Protocol Development Stage Johnson & Johnson Moloney 74 patients in ran-domized, controlled Jerome Zack and Ronald Research, Sydney, murine CD34+ cells, no phase II trial. Results expected early Mitsuyasu, UCLA Australia, NIH leukemia virus Ribozyme that targets HIV tat conditioning 2008 Carl June, University of VIRxSYS, Gaithersburg, CD4+ cells, no Two studies with 65 patients. First Pennsylvania Maryland, NIH Modified HIV Antisense that targets HIV env conditioning results expected in fall Sangamo BioSciences, CD4+ cells, no 12 patients, expected to start later this Carl June Richmond, California, NIH Adenovirus Zinc finger nucleases that target CCR5 conditioning year Donald Kohn, Children’s CD34+ cells, partial 12 patients failing therapy expected to Hospital Los Angeles NIH Modified HIV RevM10 that overrides HIV rev ablation with busulfan start in early 2008 John Rossi and John Zaia, Short RNA against HIV rev and tat, City of Hope, Duarte, ribozyme against CCR5, and TAR decoy CD34+ cells, 5 patients with AIDS lymphoma, California NIH Modified HIV against HIV tat myeloablation enrolling Dorothee von Laer, Georg- Moloney CD34+ cells, partial Speyer-Haus, Frankfurt, Fresenius Biotech, murine ablation with chemo- 5 patients with AIDS lymphoma, start Germany Vision7 GmbH, EU leukemia virus Peptide that disrupts HIV’s gp41 therapy later this year David Baltimore and Pamela Björkman, Caltech, Bill and Melinda Gates Pasadena Foundation Modified HIV Lab-designed anti-HIV antibody CD34+ cells Mouse studies Irvin Chen, UCLA NIH Modified HIV Short interfering RNA that targets CCR5 CD34+ cells Monkey studies Cohen J. Science 2007; 317:612-614 www.amfar.org 12 Zinc-finger Nuclease (ZFN)-mediated Disruption of CCR5 and Protection from HIV-1 Infection Perez EE, et al. Nature Biotechnol 2008; in press www.amfar.org Reduction in Viremia and Selection for CCR5 ZFN- modified CD4+ T-Cells in Mice Perez EE, et al. Nature Biotechnol 2008; in press www.amfar.org 13 Stable reduction of CCR5 by RNAi, with decreased susceptibility to SIV, through hematopoietic STC in rhesus macaques An DS, et al. Proc Natl Acad Sci USA 2007;104:13110-13115 www.amfar.org IV treatment with siRNA/scFvCD7-9R complexes prevents CD4+ T-cell loss and HIV replication in mice reconstituted with HIV+ human PBMCs Kumar P, et al. Cell 2008;134:577-586 www.amfar.org 14 UPCOMING amfAR GRANT OPPORTUNITIES Cycle 49 Exploring the mechanisms for HIV persistence and the potential for HIV eradication (=cure) Cycle 49 Mathilde Krim Fellows in Basic Biomedical Research Cycle 50 ARCHE renewal/continuation www.amfar.org A consortium is more than the sum of its parts: •Test an FDA-approved drug in a small clinical trial •Investigate tissue samples stored for 10 years In-person meeting of ARCHE scientists June 18, 2010 www.amfar.org 15 www.amfar.org www.amfar.org 16.